|Year : 2016 | Volume
| Issue : 3 | Page : 402-407
Palonosetron and granisetron in postoperative nausea vomiting: A randomized double-blind prospective study
Amrita A Gugale, Pradnya Milind Bhalerao
Department of Anaesthesiology and Critical Care, B. J. Government Medical College and Sassoon General Hospital, Pune, Maharashtra, India
|Date of Web Publication||27-Sep-2016|
Pradnya Milind Bhalerao
D-15/10-11, Saritanagari-2, Off, Sinhagad Road, Pune - 411 030, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Postoperative nausea and vomiting (PONV) is a common occurrence after laparoscopic surgeries. A number of pharmacological agents (antihistamines, butyrophenones, dopamine receptor antagonists) have been tried of which the 5-hydroxytryptamine type 3 receptor antagonists are devoid of most side effects and highly effective in prevention and treatment of PONV. Thus, we evaluated the effectiveness of granisetron and palonosetron in prevention of PONV after laparoscopic surgeries under general anesthesia.
Aims: We conducted a study to evaluate the effectiveness of granisetron and palonosetron, to compare the duration of action and side effects if any, in patients undergoing elective laparoscopic surgery under general anesthesia.
Settings and Design: This was a prospective, randomized, double-blinded, comparative study. Sixty patients (18–65 years of age) of the American Society of Anesthesiologists Grade I and II undergoing elective laparoscopic surgeries were considered.
Materials and Methods: They were randomly allocated into one of the two groups (Group G and Group P) of thirty patients each. Group G received injection granisetron 0.05 mg/kg; Group P received injection palonosetron 1.5 mcg/kg intravenous bolus 30 min before the induction of anesthesia.
Statistical Tests: All statistical analyses were performed using the SPSS® statistical package version 18.0 (Chicago: SPSS Inc). Two independent sample t-test was used for quantitative data, and the χ2 or Fisher's exact test was used for qualitative data. A difference was regarded as statistically significant at a P< 0.05.
Results: The need for rescue antiemetic was significantly lower in Group P in the 24–72 h postoperative period (ρ - 0.007). The PONV score was significantly less in Group P in the same period (ρ - 0.008). The incidence of side effects was statistically insignificant in both the groups (ρ - 0.999).
Conclusion: Prophylactic therapy with palonosetron is more effective than granisetron in the prevention of PONV after laparoscopic surgeries under general anesthesia.
Keywords: Granisetron, laparoscopy, palonosetron, postoperative nausea and vomiting
|How to cite this article:|
Gugale AA, Bhalerao PM. Palonosetron and granisetron in postoperative nausea vomiting: A randomized double-blind prospective study. Anesth Essays Res 2016;10:402-7
|How to cite this URL:|
Gugale AA, Bhalerao PM. Palonosetron and granisetron in postoperative nausea vomiting: A randomized double-blind prospective study. Anesth Essays Res [serial online] 2016 [cited 2019 Oct 15];10:402-7. Available from: http://www.aeronline.org/text.asp?2016/10/3/402/191121
| Introduction|| |
Postoperative nausea and vomiting (PONV) are distressing symptoms that commonly occur after surgeries under general anesthesia, the incidence being around 25% in adults, ranging from 5% to 57%. The incidence, in day care surgeries, is nearly the same varying from 8% to 45%. In addition to patient dissatisfaction, PONV may have other adverse consequences such as delayed recovery, unexpected extended hospital stay, and delayed return to work. A number of pharmacological agents (dopamine receptor antagonists, histamine antagonists, anticholinergic, serotonin antagonists, dexamethasone, and neurokinin antagonists) have been tried for the prevention and treatment of PONV with undesirable adverse effects such as excessive sedation, hypertension, dry mouth, dysphoria, hallucinations and extrapyramidal symptoms.
5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are devoid of such side effects and are highly effective in prevention and treatment of PONV. Granisetron is a highly selective and potent 5-HT3 receptor antagonist. It acts specifically at 5-HT3 receptors on the vagal afferent nerves of the gut, producing irreversible block of the 5-HT3 receptors, and may account for the long duration of this drug. Palonosetron is a unique 5-HT3 receptor antagonist having a greater binding affinity and longer half-life than other 5-HT3 antagonists such as ondansetron. Recent receptor binding studies suggest that it is further differentiated from other 5-HT3 receptor antagonists by interacting with 5-HT3 receptors in an allosteric, positively cooperative manner at sites different from those that bind with ondansetron and granisetron. This sort of receptor interaction may be associated with long-lasting effects on receptor ligand binding and functional responses to serotonin.
Laparoscopic surgeries are the preferred surgical procedures these days. These have considerably decreased the surgical mortality, but the incidence of PONV remains high. These factors reduce the quality of life of the patients and interfere with continuation of curative therapy, hence the need for prophylactic antiemetics. Treatment of PONV is thus equally important for the overall well-being of the patient in the postoperative phase.
| Materials and Methods|| |
The sample size was calculated using two independent sample proportions at 80% power. By considering the pilot study, results of complete response that is no PONV at 24–72 h (30% in Group 1 for ten cases and 70% in Group 2 for ten cases) it was estimated that minimum of 29 patients in each group would be required. In our study, thirty patients were enrolled in each group. Patients were randomly assigned to one of the two prophylactic interventions by a computer-generated number table. This prospective, randomized, double-blinded, comparative study was conducted on sixty patients undergoing elective laparoscopic surgeries either appendectomy or cholecystectomy (gynecological laparoscopic surgeries were not included in the study). Thirty patients (comparable with respect to age, sex, weight, and duration of surgery) were randomly allocated to each of the two groups. Group G received injection granisetron 0.05 mg/kg and Group P received injection palonosetron 1.5 µg/kg.
After checking all anesthesia prerequisites and valid informed consent, monitors were attached and patient premedicated with injection glycopyrrolate 0.005 mg/kg half hour prior and injection midazolam 0.03 mg/kg, injection pentazocine 0.3 mg/kg, and either of the study drug was given preinduction. After preoxygenation for 3 min, induction of anesthesia was done by injection thiopentone sodium 5 mg/kg and injection succinylcholine 2 mg/kg. Patients were intubated with appropriate size endotracheal tube and maintained on 50% oxygen, 50% nitrous oxide, isoflurane as inhalational agent, and injection vecuronium (0.08 mg/kg) as muscle relaxant. The patients were mechanically ventilated to keep end-tidal carbon dioxide (CO2) between 35 and 40 mmHg. A nasogastric tube was inserted to make the stomach empty of air and other contents. For laparoscopic surgical procedure, the peritoneal cavity was insufflated with CO2 to keep intraabdominal pressure <14 mmHg. At the end of the surgical procedure, residual neuromuscular block was adequately reversed using intravenous glycopyrrolate (0.01 mg/kg) and neostigmine (0.05 mg/kg) and subsequently extubated. Before tracheal extubation, the nasogastric tube was suctioned and removed. For postoperative analgesia, intramuscular diclofenac 75 mg was given.
All patients were observed postoperatively for 72 h (divided into intervals 0–4 h, 4–8 h, 8–12 h, 12–24 h, and 24–72 h) for number of episodes of nausea, retching, and vomiting and side effects of the study drugs.
Time to the first rescue antiemetic (injection ondansetron 0.08 mg/kg) was also noted in each group. Nausea vomiting score was also calculated (0 - no symptoms, 1 - nausea, 2 - retching, and 3 - vomiting) in each of the time intervals.
| Results|| |
Two independent sample t-test was used for quantitative data, and the χ2 or Fisher's exact test was used for qualitative data. A difference was regarded as statistically significant at a ρ < 0.05.
The study was assessed in terms of, incidence of PONV (nausea, retching, and vomiting and the time in hours when each of these occurred), number of patients requiring rescue antiemetic and time at which first rescue antiemetic was given and details of any side effects such as headache, dizziness, and drowsiness were also observed.
The demographic data (age, sex, and weight) and duration of surgery were found to be statistically comparable [Figure 1], [Figure 2], [Figure 3] and [Table 1], [Table 2], [Table 3]. The number of patients requiring rescue antiemetic was statistically not significant in both the groups in the first 24 h, but was highly statistically significant in the 24–72 h period in the granisetron group [Figure 4] and [Table 4]. Thus, it proved that patients who had received palonosetron had lesser requirement of rescue antiemetic overall and significantly less in the 24–72 h period. In addition, the PONV score was much less in the palonosetron group implying that these patients had fewer episodes of PONV [Figure 5] and [Table 5].
|Table 1: Demographic characteristics and comparison of age between study groups|
Click here to view
The incidence of PONV in granisetron group was found to be maximum in the 24–72 h period (56.66%). The incidence of PONV in palonosetron group was also found to be maximum in the 24–72 h period but in less number of patients (20%) [Table 6]. The side effect profile of both the drugs was also comparable and statistically not significant [Table 7].
| Discussion|| |
Etiopathogenesis of PONV is very complex in nature and is triggered by multiple inputs that arrive from multiple areas. Preoperative anxiety, positive pressure ventilation, inhalational anesthetic agents, and nitrous oxide increase the risk of PONV. Anesthetic agents initiate the vomiting reflex by stimulating the central 5-HT3 receptors on the chemoreceptor trigger zone. PONV is more common in younger age group and in obese patients., Laparoscopic surgery, female gender, nonsmokers, a history of PONV, motion sickness, and postoperative opioid therapy are considered as important independent causal factors for PONV. The incidence of PONV after laparoscopy has however been found to be almost the same than after an open procedure.
Peripheral 5-HT3 receptors are in vagal terminals and are linked to the vomiting center, and competitive 5-HT3 antagonists can block initiation of the vomiting reflex at these sites. Selective 5-HT3 receptor antagonists (granisetron and palonosetron) have a well-established role in the prophylaxis and treatment of PONV. They have greater efficacy as well as a better safety and side effect profile compared with traditional antiemetic agents.
Granisetron produces irreversible block of the 5-HT3 receptors, and it may account for the long duration of this drug., Palonosetron shows avid binding to the 5-HT3 receptor which far exceeds than the other 5-HT3 antagonists and has the longest elimination half-life of 40 h. We did not choose a placebo group as a control group in our study because the patients we chose were having a 40% risk of developing PONV and denial of effective antiemetic treatment was unjustified and unethical. Fuji et al. observed that during the 24 h after recovery from anesthesia, the frequencies of postoperative retching and vomiting in patients who had received granisetron were lower than those who had received placebo and the severity of postoperative vomiting was reduced with the administration of granisetron.
The effective dose of granisetron used in this study was 50 µg/kg. Fuji et al. demonstrated that granisetron is superior to metoclopramide in prevention of PONV after general anesthesia, and optimum antiemetic dose is 40 µg/kg.
Candiotti et al. demonstrated that palonosetron 75 µg is more effective dose for the prevention of PONV after major gynecological and laparoscopic surgery than 25 µg and 50 µg in the 0–48 h period. Kovac et al. also found that palonosetron 75 µg was more effective than placebo in the 72 h postoperative period in female patients undergoing elective gynecological and breast surgery. Hence, we used dose of palonosetron 1.5 µg/kg in our study which was more than or equal to 75 µg depending on the patients weight.
In our study, we randomized all the patients into two groups; Group G (granisetron) and Group P (palonosetron) to avoid results getting affected by demographic factors (age, sex, weight, and duration of surgery). There is no statistically significant difference in the patients in both the groups with relation to above factors.
In the first 4 h, our study showed incidence of PONV that was 16.6% in granisetron group (Group G) and 10% in palonosetron group (Group P), 4–8 h incidence was 6.6% in Group G, and 0% in Group P. PONV incidences in 8–12 and 12–24 h were 6.66% each for Group G. In Group P, incidences of PONV in 8–12 h was 3.3% and in 12–24 h was 13.33%. Last, incidences of PONV were maximum in the 24–72 h period, 56.6% for Group G, and 20% in Group P. This implied that the maximum incidence of PONV was observed in late postoperative period.
These incidences of PONV are comparable to the findings of Bhattacharjee et al. in 2010. The incidence of PONV in Group G in 0–3 h was 23.3% and in Group P was 13.33% which is comparable to our study in the 0–4 h period in both groups. While PONV incidence in their study was 26.66% for Group G and 16.6% for Group P, the period was from 3 to 24 h. Still, this incidence is also comparable to our overall incidence of 19.8% in Group G and 16.6% in Group P if we consider the 4–24 h period. Last, similar to our study, the incidence of PONV was maximum in the 24–48 h period with 43.3% patients experiencing PONV in Group G and 16.66% in Group P. Our values of PONV of 56.6% in Group G and 20% in Group P are slightly higher and this may be attributable to our longer observation period of up to 72 h postoperatively, leading to slightly more number of patients experiencing PONV.
In the study conducted by Candiotti et al., incidence of PONV was 26% between 0 and 24 h and 51% in 24–48 h in patients who received 0.075 mg palonosetron before induction as compared to 57% and 59%, respectively in patients who received placebo. This value is higher than that observed in our study (26.6% in 0–24 h and 33.3% in 24–72 h in palonosetron group) and may be due to difference in surgical technique, intraoperative use of different anesthetic drugs, positional changes, the suctioning at the time of extubation, and residual pneumoperitoneum. Kovac et al. found incidence of PONV 44% in patients receiving palonosetron 0.075 mg in 0–24 h and 30% in 24–48 h. The value is slightly higher in the 0–24 h period but is comparable to our study in the 24–48 h period (26.6% in 0–24 h and 33.3% in 24–72 h.)
Adverse effects with a single therapeutic dose of granisetron and palonosetron were not statistically significant. The incidence of headache, dizziness, and drowsiness was only 13.3% each in both the groups (granisetron group had 13.3% incidence of dizziness and palonosetron group had 6.6% patients with headache and 6.6% patients with dizziness). This is similar to incidence found in study of Bhattacharjee et al.
In the present study, rescue antiemetic was needed in 70% and 20% patients in granisetron and palonosetron group, respectively in 0–72 h (ρ - 0.007 which is highly significant in the 24–72 h period). Rescue antiemetic was administered in our study when retching or vomiting occurred or on patient's request. This is not consistent with Bhattacharjee et al. in which no rescue antiemetic was required in 0–48 h in both groups. This may be due to their study design followed criteria where rescue antiemetic was administered if two or more episodes of PONV occurred during first 48 h. In addition, our study included a longer period of observation up to 72 h postoperatively leading to greater administration of rescue antiemetic in the 24–72 h period as the antiemetic efficacy of the study drugs will gradually be reduced beyond 24 h. In the study conducted by Candiotti et al. requirement of rescue antiemetic was 52% in placebo group and 44% in palonosetron group, whereas the study by Kovac et al. showed requirement as 46% in placebo group and 27% in palonosetron group.,
A significant difference of PONV score was noted in both our groups in 0–72 h (P < 0.05) with mean PONV score of 3.97 and 1.67 in the granisetron and palonosetron groups, respectively. Our study thus proves that the PONV score is significantly less in the palonosetron group as compared to granisetron group. Ghosh et al. used a similar scale of PONV score and observed a better antiemetic response, score of 0 in the palonosetron group from 0 to 24 h, whereas a score of 1 was seen in five patients in this group in 24–48 h. Their study concluded that palonosetron was as effective as palonosetron in combination with dexamethasone.
Our study thus demonstrates that the antiemetic efficacy of palonosetron is similar to granisetron in the first 24 h after laparoscopic surgeries. However, in the 24–72 h period, palonosetron is significantly better in its antiemetic efficacy than granisetron. This suggests that palonosetron has an antiemetic effect which lasts longer than granisetron. The exact reason for the difference in effectiveness is not known but may be related to the half-lives (granisetron 8–9 h vs. palonosetron 40 h) and/or binding affinities of 5-HT3 receptor antagonists (palonosetron interacting with 5-HT3 receptors in an allosteric, positively cooperative manner at sites different from those that bind with ondansetron and granisetron).,
| Conclusion|| |
Thus, palonosetron is more effective in the prevention of PONV in patients undergoing elective laparoscopic surgeries under general anesthesia as compared to granisetron, especially in the 24–72 h period postoperatively. The least PONV score was also observed with palonosetron in the 24–72 h period postoperatively.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Amandeep K, Kataria A. Comparative evaluation of granisetron versus palonosetron to prevent postoperative nausea and vomiting after open cholecystectomy. J Evol Med Dent Sci 2014;62:13717-22.
Gupta K, Singh I, Gupta PK, Chauhan H, Jain M, Rastogi B. Palonosetron, ondansetron, and granisetron for antiemetic prophylaxis of postoperative nausea and vomiting – A comparative evaluation. Anesth Essays Res 2014;8:197-201.
Newberry NR, Watkins CJ, Sprosen TS, Blackburn TP, Grahame-Smith DG, Leslie RA. BRL 46470 potently antagonizes neural responses activated by 5-HT3 receptors. Neuropharmacology 1993;32:729-35.
Gralla R, Lichinitser M, Van Der Vegt S, Sleeboom H, Mezger J, Peschel C, et al.
Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: Results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol 2003;14:1570-7.
Leslie K, Myles PS, Chan MT, Paech MJ, Peyton P, Forbes A, et al.
Risk factors for severe postoperative nausea and vomiting in a randomized trial of nitrous oxide-based vs nitrous oxide-free anaesthesia. Br J Anaesth 2008;101:498-505.
Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg 2006;102:1884-98.
Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, et al.
A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441-51.
Hargitai B, Stangl R, Szebeni Z, Nagy E, Darvas K, Kupcsulik P. The risk of PONV in patients undergoing laparoscopic cholecystectomy. Eur J Anaesthesiol 2006;23:11.
Fujii Y, Tanaka H, Toyooka H. Granisetron reduces vomiting after strabismus surgery and tonsillectomy in children. Can J Anaesth 1996;43:35-8.
Bicer C, Aksu R, Ulgey A, Madenoglu H, Dogan H, Yildiz K, et al.
Different doses of palonosetron for the prevention of postoperative nausea and vomiting in children undergoing strabismus surgery. Drugs R D 2011;11:29-36.
Fuji Y, Tanaka H, Toyooka H. Optimal antiemetic dose of granisetron for prevention of post operative nausea and vomiting. Can J Anaesth 1994;41:9, 749-57.
Candiotti KA, Kovac AL, Melson TI, Clerici G, Joo Gan T; Palonosetron – Study Group. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg 2008;107:445-51.
Kovac AL, Eberhart L, Kotarski J, Clerici G, Apfel C; Palonosetron – Study Group. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg 2008;107:439-44.
Bhattacharjee DP, Dawn S, Nayak S, Roy PR, Acharya A, Dey R. A comparative study between palonosetron and granisetron to prevent postoperative nausea and vomiting after laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol 2010;26:480-3.
Ghosh S, Pal A, Acharya A, Biswas C, Ghosh TR, Ghosh S. Palonosetron and palonosetron plus dexamethasone to prevent postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A prospective, randomized, double-blind comparative study. Anesth Essays Res 2011;5:134-7.
Ho KY, Gan TJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol 2006;19:606-11.
Rojas C, Stathis M, Thomas AG, Massuda EB, Alt J, Zhang J, et al.
Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg 2008;107:469-78.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]